Arrhythmogenic Right Ventricular Dysplasia, Familial, 10

A number sign (#) is used with this entry because of evidence that arrhythmogenic right ventricular dysplasia-10 (ARVD10) is caused by heterozygous mutation in the desmoglein-2 gene (DSG2; 125671) on chromosome 18q12.

For a phenotypic description and a discussion of genetic heterogeneity of ARVD, see ARVD1 (107970).

Molecular Genetics

Pilichou et al. (2006) analyzed the DSG2 gene in 54 probands of Italian descent with arrhythmogenic right ventricular cardiomyopathy who were negative for mutations in the TGFB3 (190230), DSP (125647), and PKP2 (602861) genes, and identified 5 missense mutations, 2 insertion-deletions, 1 nonsense mutation, and 1 splice site mutation. The mutations were found in heterozygosity in 7 probands (see, e.g., 125671.0006) and in compound heterozygosity in 1 proband (125671.0007-125671.0008). None of the patients had effort-induced polymorphic ventricular arrhythmias or gross skin/hair abnormalities. Endomyocardial biopsies performed in 5 mutation-positive patients revealed a mean area of residual myocardium of approximately 47%, fibrous tissue of 24%, and fatty tissue of 20%. Electron microscopy in 3 of the biopsied patients revealed a decreased desmosome number, intercalated disc paleness, and intercellular gap widening.

Awad et al. (2006) identified 33 cases of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) in which no mutation in the PKP2 or DSP genes had been found. Amplification and sequencing of the exonic and adjacent intronic sequence of the entire DSG2 gene identified mutations in 4 individuals. Three of the 4 probands had a heterozygous missense mutation in DSG2. The fourth proband had a missense mutation on 1 DSG2 allele and a nonsense mutation on the other (see 125671.0001). His unaffected mother and sister shared the nonsense mutation. Awad et al. (2006) suggested that this could indicate incomplete penetrance, or that this mutation is insufficient to result in ARVD/C in isolation.

Syrris et al. (2007) sequenced the DSG2 gene in 86 Caucasian ARVC patients known to be negative for mutations in the DSP, PKP2, and JUP (173325) genes and detected 8 mutations in 9 probands (see, e.g., V55M, 125671.0009); the mutations were not found in 400 control chromosomes. Clinical evaluation of 24 family members with DSG2 mutations demonstrated penetrance of 58 to 75%, depending on the criteria used. Morphologic abnormalities of the right ventricle were evident in 66% of mutation carriers, left ventricular involvement in 25%, and classic right precordial T-wave inversion in only 26%. Sustained ventricular arrhythmia was present in 8%, and a family history of sudden death or aborted sudden death in 66%. Syrris et al. (2007) concluded that mutations in DSG2 show a high degree of penetrance with variable severity of expression; regarding the low prevalence of classic ECG changes, the authors suggested that current diagnostic criteria be expanded to account for left ventricular disease, childhood disease expression, and incomplete penetrance.